Inflammation is a common feature of a number of neurodegenerative diseases including Alzheimer's disease (AD) wherein inflammatory processes with significant contribution by vascular changes play a role in disease pathogenesis. Recent genetic, experimental and epidemiological findings further suggest a link between vascular risk factors including hypertension, diabetes, atherosclerosis and hypercholesterolemia and the development of AD. We propose that atherogenic inflammation resulting from a dysregulation of cholesterol homeostasis due to dietary and/or genetic causes may adversely affect the brain vasculature, leading to AD-associated cognitive impairment. The proposed studies will examine if targeted disruption of a signaling pathway i.e., p38 MAP kinase, that is critically involved in inflammatory cascades would ameliorate hypercholesterolemia-induced neurovascular inflammation and cognitive impairment in a mouse model of AD. The experiments will use transgenic mice expressing mutant human amyloid precursor protein (APPTg) made deficient in a key member of the p38 MAP kinase cascade i.e., MAPK-activated protein kinase 2 (i.e., MAPKAP K2 or MK2) to test the hypothesis that this pathway signals atherogenic induction of neurovascular and inflammatory changes leading to AD-like dementia. The specific objectives are to determine if the kinase depletion and pharmacological intervention reduce dietary cholesterol-induced neuroinflammation and increased amyloid deposition in the APPTg mice with the outcome of an improved cognitive performance. The findings will have implications for designing therapeutic strategies targeted towards neurovascular inflammatory processes in AD. PUBLIC HEALTH RELEVANCE: Atherogenic inflammation resulting from a dysregulation of cholesterol homeostasis due to dietary and/or genetic causes may adversely affect the brain vasculature leading to Alzheimer's disease (AD)-associated cognitive impairment. The proposed studies explore the idea that targeted disruption (genetic or pharmacological) of a key proinflammatory signaling pathway i.e., p38 MAP kinase, would ameliorate AD-like brain changes in a mouse model of AD with hypercholesterolemia. The findings would define a functional link between hypercholesterolemia-induced systemic immune response, brain function and behavior.